Project Grant R44CA278021

ALLOGENEIC BAFF LIGAND BASED CAR T CELLS AS A NOVEL THERAPY FOR B CELL MALIGNANCIES - ABSTRACT SINCE THE FIRST FDA APPROVAL OF CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY IN 2017, THE USE OF ENGINEERED T CELLS EXPRESSING SPECIFIC CARS TO TREAT CANCER HAS GENERATED DURABLE CURES FOR MANY PATIENTS. NEVERTHELESS, A SIGNIFICANT SUBSET OF PATIENTS WITH B CELL MALIGNANCIES RELAPSE FOLLOWING TREATMENT DUE TO LACK OF CAR T CELL PERSISTENCE AND THE ABILITY OF CANCER CELLS TO CHANGE WITH TIME AND EVADE THERAPEUTIC INTERVENTIONS. AUTOLOGOUS T CELL THERAPIES ALSO CARRY SIGNIFICANT TIMELINE AND COST BURDENS, MAKING WIDESPREAD ADOPTION DIFFICULT. IN THIS APPLICATION, WE PROPOSE A NOVEL ALLOGENEIC CAR T CELL THERAPY AIMED AT IMPROVING OUTCOMES FOR PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) BY OVERCOMING DEFICIENCIES PRESENT IN CURRENT GENERATION CD19 TARGETED THERAPEUTICS. B CELL ACTIVATING FACTOR (BAFF) PROVIDES CRITICAL SURVIVAL SIGNALS TO BOTH NORMAL AND NEOPLASTIC B CELLS THROUGH A FAMILY OF RECEPTORS (BAFF RECEPTOR, TACI, AND BCMA) THUS MITIGATING POTENTIAL FOR ANTIGEN ESCAPE. BAFF AND ITS RECEPTORS HAVE REMAINED UNDEREXPLORED IN THE CONTEXT OF B CELL MALIGNANCIES WHERE STRATEGIES HAVE RELIED OVERWHELMINGLY ON PAN B CELL ANTIGENS SUCH AS CD19 AND CD20. SINCE BAFF BINDS ITS RECEPTORS WITH MODERATE AFFINITY, WE BELIEVE THIS WILL INCREASE THE ABILITY OF THESE CELLS TO FORM MEMORY POPULATIONS AND ENGAGE IN SERIAL KILLING. WE WILL LEVERAGE THIS LIGAND-BASED CAR DESIGN IN AN ALLOGENEIC GAMMA DELTA (D) T CELL PLATFORM, AS D T CELLS HAVE BEEN SHOWN TO HAVE HIGH REPLICATIVE PROPERTIES IN VITRO AND DO NOT MEDIATE GRAFT VERSUS HOST DISEASE IN NEW HOSTS. WE HAVE PRODUCED PRELIMINARY DATA THAT CONFIRMS OUR ABILITY TO USE THE NON- VIRAL TCBUSTER DNA TRANSPOSON SYSTEM TO GENERATE T CELLS WITH BAFF-CAR EXPRESSION. THE OVERALL OBJECTIVE OF THIS PROPOSAL IS TO FURTHER DEVELOP AND EVALUATE OUR D BAFF-CAR T CELL THERAPY FOR THE TREATMENT OF MCL IN IND ENABLING STUDIES. IN DOING SO, OUR ALLOGENEIC BAFF-CAR T CELL THERAPY SUPPORTS AN URGENTLY NEEDED SHIFT IN THERAPEUTIC DEVELOPMENT TOWARD NEW TUMOR ANTIGENS THAT PROTECT AGAINST ANTIGEN ESCAPE WHILE REDUCING THE MANUFACTURING BURDEN ASSOCIATED WITH CELLULAR THERAPIES THROUGH USE OF A READILY AVAILABLE CELL SOURCE.